Complications of cardiovascular disease, such as myocardial infarction, stroke, and peripheral vascular disease account for about half of the deaths in the United States. A high level of low density lipoprotein (LDL) in the bloodstream has been linked to the formation of coronary lesions that obstruct the flow of blood and can rupture and promote thrombosis. Goodman and Gilman, The Pharmacological Basis of Therapeutics 879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and in patients who are free of cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatic Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b. In addition, low levels of high density lipoprotein (HDL) and high levels of triglycerides (TG) are also known to be associated with increased incidence of cardiovascular disease and primary and secondary coronary events including, but not limited to, myocardial infarction.
Statins are currently among the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. Statins are also known to raise HDL cholesterol levels and decrease total triglyceride levels. Specific examples of statins include, inter alia, compactin, lovastatin, mevastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, itavastatin and fluvastatin. The mechanism of action of statins has been elucidated in some detail. It is believed that statins disrupt the biosynthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoA reductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Consequently, its inhibition leads to a reduction in the rate of formation of cholesterol in the liver.
Pravastatin is the common name of the chemical compound [1S-[1α(βS*,δS*)2α, 6α,8β(R*),8aα]]-1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid monosodium salt, disclosed in U.S. Pat. No. 4,346,227 to Terahara et al.
Pharmaceutical compositions that include a medicament that is unstable in an acidic environment have been thought to require a basic excipient to enhance storage stability. For example, pravastatin sodium is an HMG-CoA reductase inhibitor having the structural formula:

Pravastatin sodium (sold in the U.S. under the trademark PRAVACHOL®) is sensitive to a low pH environment and will degrade to form its lactone and various isomers. Joshi et al. stated in U.S. Pat. No. 5,180,589 that it is necessary to add one or more basifying agents to impart a desired pH of at least 9 to an aqueous dispersion of a pravastatin composition in order to stabilize it. Among the basifying agents disclosed in U.S. Pat. No. 5,180,589 are magnesium oxide, aluminum oxide, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide and alkaline earth metal hydroxides such as calcium hydroxide or magnesium hydroxide. Magnesium oxide is said to be the preferred basifying agent. Thus, the types of basifying agents disclosed in U.S. Pat. No. 5,180,589 as stabilizing agents are inorganic metal oxides and hydroxides, which are generally considered to be strongly alkaline agents.
Atorvastatin calcium, another HMG-CoA reductase inhibitor, is described in U.S. Pat. No. 5,273,995 to Roth. Atorvastatin calcium is [R-(R*,R*)-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1 -methylethyl)-3 -phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid, hemicalcium salt, and has the following structural formula:

Atorvastatin calcium (sold in the U.S. under the trademark LIPITOR®) is susceptible to a low pH environment and can degrade to the corresponding lactone in an acidic environment. Mills et al. have stated in U.S. Pat. No. 5,686,104 that this and similar compounds in an oral pharmaceutical formulation for the treatment of hypercholesterolemia or hyperlipidemia are stabilized by combination with at least one basic inorganic pharmaceutically acceptable calcium, magnesium, aluminum or lithium salt. Examples of these salts are calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide or lithium hydroxide. Calcium hydroxide is disclosed as the preferred alkaline earth stabilizing agent. Thus, as in U.S. Pat. No. 5,180,589, the stabilizing agents disclosed in U.S. Pat. No. 5,686,104 are basic inorganic pharmaceutically acceptable salts.
WO 00/35425 discloses the stabilization of an HMG-CoA reductase inhibitor in a solid formulation with a buffering agent. Among the buffering agents disclosed in WO 00/35425 are sodium or potassium citrate, sodium phosphate, dibasic sodium phosphate, calcium carbonate, hydrogen phosphate, phosphate, sulphate, sodium or magnesium carbonate, sodium ascorbinate, benzoate, sodium or potassium hydrogen carbonate, lauryl sulphate, or mixtures of such buffering agents. Among the HMG-CoA reductase inhibitors disclosed in WO 00/34525 are atorvastatin, pravastatin, fluvastatin and cerivastatin, which are said to be particularly sensitive to an acidic environment in which hydroxy acids are degraded into the corresponding lactone.
As used herein, the term “dyslipidemia” refers to an abnormal level of one or more of total cholesterol (Total-C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (Apo B), apolipoprotein A (Apo A), very low density lipoprotein cholesterol (VLDL-C), and intermediate density lipoprotein cholesterol (IDL-C). By “abnormal” is meant a level generally accepted by the relevant medical community as an undesirable level, which may be higher or lower than desirable, and which may be beneficially adjusted by treatment of a patient with a stabilized statin composition as disclosed herein. Guidelines for the detection, evaluation and treatment of dyslipidemias are promulgated by the National Institute of Health's National Cholesterol Education Program (“NCEP”). The NCEP guidelines suggest when treatment with therapeutic agents such as the statin compounds disclosed herein, are indicated for the treatment of a dyslipidemia such as hypercholesterolemia. Initiation of treatment with a statin compound, in accordance with the NCEP guidelines depends on numerous factors. Among such factors are included abnormal levels of one or more of Total-C, LDL-D, TG, Apo B, Apo A, VLDL-C and IDL-C; familial history of cardiovascular disease or event; prior cardiovascular disease; and, prior occurrence of an acute cardiovascular event, such as myocardial infarction, etc.
By “therapeutically effective amount” as used herein is meant an amount of active component in the stabilized pharmaceutical compositions of the present invention which is effective to beneficially treat a dyslipidemia.
The term “dyslipidemia” thus encompasses “hyperlipidemia”, “hypercholesterolemia” and “hypertriglyceridemia” which terms as used herein refer to abnormally high levels of one or more of Total-C, LDL-C, TG, Apo B, VLDL-C and IDL-C. Thus, the term “dyslipidemia” includes all of the dyslipidemias classified by the Frederickson Classification System, including Frederickson Type I hyperlipidemia, Frederickson Types Ia and IIb primary hypercholesterolemia, Frederickson Type IV hypertriglyceridemia, Frederickson Type III dysbetaliproteinemia, and Frederickson Type V hyperlipidemia.
By “stabilized pharmaceutical composition” as used herein is meant that after storage for six months at 40° C. and 75% relative humidity, no more than about 10%, preferably no more than about 5%, and more preferably, no more than about 1% by weight of the active component initially present in the composition degrades into the corresponding lactone.
By “stabilizing effective amount” as used herein is meant an amount by weight of a stabilizing compound present in the pharmaceutical composition which is effective to provide a stabilized pharmaceutical composition.
By “stabilizing effective amount of another stabilizer or a combination of other stabilizers” as used herein is meant an amount of a stabilizing compound or combination of stabilizing compounds, other than the amido-group containing polymeric stabilizing compound or compounds as used in the pharmaceutical compositions of the subject invention, which would provide a stabilized pharmaceutical composition as defined herein. Thus, the present invention is not meant to be construed as excluding compounds that may provide some stabilizing effect, but only to exclude a stabilizing effective amount of one or more of such compounds As disclosed hereinabove, other such stabilizing compounds include, for example, inorganic alkaline and alkaline earth metal salts, oxides and hydroxides as disclosed, for example, in U.S. Pat. No. 5,180,589; U.S. Pat. No. 5,686,104, and buffering agents as disclosed, for example, in WO 00/34525.
By “amido-group containing polymeric compound” as used herein is meant a pharmaceutically acceptable polymeric compound containing, either in a pendant group attached to the polymer backbone, or as a component of the polymer backbone, an amido group, i.e., a group having the formula:
wherein the carbon atom is bonded to another atom and the nitrogen atom is bonded to two other atoms. The term “amido-group containing polymeric compound” is meant to include combinations of different amido-group containing polymeric compounds. Preferred amido-group containing polymeric compounds are those in which nitrogen and carbon are covalently bonded to atoms other than hydrogen. By “tertiary amide group” as used herein is meant an amido-group in which nitrogen is covalently bonded, not including its bond to the carbonyl group, to two atoms neither of which is hydrogen.
By “amino-group containing polymeric compound” as used herein is meant a pharmaceutically acceptable polymeric compound containing, either in a pendant group attached to the polymer backbone, or as a component of the polymer backbone, an amino group, i.e., a group having the formula:
wherein the nitrogen atom is bonded to three other atoms. The term “amino-group containing polymeric compound” is meant to include combinations of different amino-group containing polymeric compounds.” Preferred amino-group containing polymeric compounds are those in which the nitrogen atom is covalently bonded to atoms other than hydrogen. Particularly preferred amino-group containing polymeric compounds are those in which the amino group is quaternized, in which case, the amino-group containing polymeric compounds can be equivalently described an a quaternary ammonium salt group containing polymeric compound. The agent used to quaternize the amino group is not critical. Methyl chloride is a preferred quaternizing agent, however, any chemical reagent which is pharmaceutically acceptable and which forms a quaternary ammonium salt by reaction with a tertiary amino group may be used. As examples of quaternizing agents may be mentioned, without limitation, C1-C3 straight or branched chain alkyl halides, phosphates, carbonates, or sulfates; C7-C10 aralkyl halides, phosphates or sulfates, and mixtures thereof. Examples of preferred quaternizing agens include but are not limited to methyl chloride, benzyl chloride, diethyl sulfate, dimethyl carbonate, trimethyl phosphate, dimethyl sulfate or mixtures thereof. By “tertiary amino group” as used herein is meant an amino group in which nitrogen is covalently bonded three atoms none of which are hydrogen.
By “aqueous dispersion” as used herein in reference to measurement of the pH of the stabilized pharmaceutical compositions of the present invention is meant an amount of a stabilized pharmaceutical composition of the present invention disintegrated in an amount of deionized water sufficient to provide a concentration of active component of about 1 mg/ml